PROJECT SUMMARY Opioid overdoses have reached epidemic proportions in the United States. Our research team, along with other groups, has identified key populations at risk for opioid overdose, including people with HIV, substance use disorders, and mental health conditions. Naloxone is an effective opioid antidote which reverses opioid overdose. Traditionally used by medical personnel, naloxone for take-home use is gaining wider acceptance to prevent death among people who use drugs. Yet, take-home naloxone may also reduce the risk of overdose death among patients prescribed opioids for pain. Our study will examine the safety and impact of expanded access to naloxone for patients prescribed opioids in two large and diverse health systems. These health system pharmacies serve many key risk groups for overdose. While naloxone delivered through health system pharmacies is likely to prevent overdose fatalities, our developmental research has identified critical barriers to wide scale adoption of this practice. These include medical provider concerns that naloxone will increase risk behavior and that patients may not acquire adequate knowledge to effectively use the medication and educate potential bystanders. In addition, providers had concerns about adverse health outcomes associated with naloxone use among patients with co-morbidities. The proposed research will address these key evidence gaps. We will conduct a clustered randomized pragmatic trial of co-dispensing naloxone with opioids under new standing order legislation passed in Colorado. This trial will be conducted in an integrated safety net network of community health centers and hospital and in a large managed care organization. Our outcomes will include opioid risk behavior, overdose and naloxone knowledge, and overdose rates. This will be followed by a qualitative investigation into overdose and naloxone use among people dispensed naloxone to elucidate knowledge gaps, process failures, and unanticipated adverse outcomes. Finally, we will conduct a post- implementation safety assessment of naloxone to examine the risk of adverse health outcomes using novel self-controlled analytic techniques. Together, these aims will provide a comprehensive assessment of the impact and safety of expanded access naloxone for patients prescribed opioids in HIV and other primary care settings.